Liraglutide Improves Cognitive and Neuronal Function in 3-NP Rat Model of Huntington’s Disease

Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor, psychiatric, and cognitive abnormalities. The antidiabetic drug liraglutide possesses a neuroprotective potential against several neurodegenerative disorders; however, its role in Huntington’s disease (HD) and the possible mechanisms/trajectories remain elusive, which is the aim of this work. Liraglutide (200 μg/kg, s.c) was administered to rats intoxicated with 3-nitropropionic acid (3-NP) for 4 weeks post HD model induction. Liraglutide abated the 3-NP-induced neurobehavioral deficits (open field and elevated plus maze tests) and histopathological changes. Liraglutide downregulated the striatal mRNA expression of HSP 27, PBR, and GFAP, while it upregulated that of DARPP32. On the molecular level, liraglutide enhanced striatal miR-130a gene expression and TrKB protein expression and its ligand BDNF, while it reduced the striatal protein content and mRNA expression of the death receptors sortilin and p75NTR, respectively. It enhanced the neuroprotective molecules cAMP, p-PI3K, p-Akt, and p-CREB, besides modulating the p-GSK-3β/p-β-catenin axis. Liraglutide enhanced the antioxidant transcription factor Nrf2, abrogated TBARS, upregulated both Bcl2 and Bcl-XL, and downregulated Bax along with decreasing caspase-3 activity. Therefore, liraglutide exerts a neurotherapeutic effect on 3-NP-treated rats that is, besides the upturn of behavioral and structural findings, it at least partially, increased miR-130a and modulated PI3K/Akt/CREB/BDNF/TrKB, sortilin, and p75NTR, and Akt/GSK-3β/p-β-catenin trajectories besides its capacity to decrease apoptosis and oxidative stress, as well as its neurotrophic activity.

Download Full-text

Neuroprotective potential of Cilostazol in 3-NP provoked Huntington's disease-associated symptoms

Research Journal of Pharmacy and Technology ◽

10.52711/0974-360x.2021.00435 ◽

2021 ◽

pp. 2472-2478

Author(s):

Surbhi Gupta ◽

Bhupesh Sharma

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neuronal Damage ◽

Lipid Peroxides ◽

Acetylcholinesterase Activity ◽

Nitropropionic Acid ◽

Behavioral Abnormalities ◽

Plus Maze ◽

Nissl Stain ◽

And Behavior

Huntington's disease (HD), a neurodegenerative condition specified by mitochondrial deficits, psychiatric and cognitive impairment developed due to neuronal damage in the brain. 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase develops behavioral, biochemical as well as histological alterations in the striatal region of brain, which resembles HD in humans. Phosphodiesterases (PDEs) participate in cognition, motor functions, and behavior as well as also offers neuroprotection. The present investigation was framed to analyze the neuro-defensive characteristics of cilostazol PDE3 inhibitor over the 3-NP induced behavioral, striatal and mitochondrial deficits. Administration of 3-NP (10mg kg-1; i.p.) for the duration of 14 days has shown considerable alterations in behavior such as decreased locomotion (actophotometer), reduced grip strength (rota-rod test), spatial learning memory (elevated plus maze and Morris water maze). In parallel to, 3-NP treated rats exhibit biochemical changes such as increased oxidative stress (enhanced lipid peroxides, reduced glutathione, catalase, and superoxide dismutase), disturbed cholinergic function (increased acetylcholinesterase activity), increased inflammation (more myeloperoxidase) and mitochondrial dysfunction (reduced complex I, II and IV activity). Histopathological changes (Nissl stain) like chronic neuronal gap, pyknotic nuclei as well as injured cells in the cerebral cortex and hippocampus were also observed in 3-NP treated rats. Administration of cilostazol considerably restored behavioral abnormalities, biochemical and histopathological alterations. In this investigation, cilostazol offered neurodefensive effects which were established by behavioral and biochemical paradigms, which confirmed the potent neurodefensive aspect of cilostazol in 3-NP provoked behavioral and biochemical abnormalities.

Download Full-text

Striatal Neurodegeneration that Mimics Huntington’s Disease Modifies GABA-induced Currents

Brain Sciences ◽

10.3390/brainsci8120217 ◽

2018 ◽

Vol 8 (12) ◽

pp. 217

Author(s):

Jorge Flores-Hernández ◽

Jeanette Garzón-Vázquez ◽

Gustavo Hernández-Carballo ◽

Elizabeth Nieto-Mendoza ◽

Evelyn Ruíz-Luna ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Gaba Receptors ◽

Gaba Receptor ◽

Receptor Subtype ◽

Medium Spiny Neurons ◽

Nitropropionic Acid ◽

Spiny Neurons ◽

Excitotoxic Damage ◽

Induced Currents

Huntington’s Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABAC receptors in MSNs. Furthermore, there was a reduction in the effect of the GABAC antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition.

Download Full-text